Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline

Schwarz, Claudia; Stekovic, Slaven; Wirth, Miranka; Benson, Gloria; Royer, P; Sigrist, Stephan J.; Pieber, Thomas R.; Dammbrueck, Christopher; Magnes, Christoph; Eisenberg, Tobias; Pendl, Tobias; Bohlken, Jens; Köbe, Theresa; Madeo, Frank; Flöel, Agnes

doi:10.18632/aging.101354

Cited by 114 publications

(107 citation statements)

References 38 publications

(41 reference statements)

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“…Spermidine has recently been administered to humans in a small experimental trial with a beneficial effect on cognitive function without adverse effects 36,37 . It remains to be shown whether at such low doses it has an effect on autophagy.…”

Section: Discussionmentioning

confidence: 99%

Autophagy in T cells from aged donors is maintained by spermidine, and correlates with function and vaccine responses

Alsaleh

Panse

Swadling

et al. 2020

Preprint

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Older adults are at high risk for infectious diseases such as the recent and vaccination seems to be the only long-term solution to the pandemic. While most vaccines are less efficacious in older adults, little is known about the molecular mechanisms that underpin this. Autophagy, a major degradation pathway and one of the few processes known to prevent aging, is critical for the maintenance of immune memory in mice. Here, we show induction of autophagy is specifically induced in human vaccine-induced antigen-specific T cells in vivo. Reduced IFNg secretion by vaccine-induced T cells in older vaccinees correlateswith low autophagy. We demonstrate in human cohorts that levels of the endogenous autophagy-inducing metabolite spermidine, fall with age and supplementing it in vitro recovers autophagy and T cell function. Finally, our data show that endogenous spermidine maintains autophagy via the translation factor eIF5A and transcription factor TFEB. With these findings we have uncovered novel targets and biomarkers for the development of anti-aging drugs for human T cells, providing evidence for the use of spermidine in improving vaccine immunogenicity in the aged human population.Alsaleh, Panse et al

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Section: Discussionmentioning

confidence: 99%

Autophagy in T cells from aged donors is maintained by spermidine, and correlates with function and vaccine responses

Alsaleh

Panse

Swadling

et al. 2020

Preprint

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“…N1-acetylspermine (N1-AcSpm) and N1-acetylspermidine (N1-AcSpd) are synthesized by the transfer of an acetyl group from acetyl-coenzyme A to the N1-position of either Spd or Spm, respectively, which is catalyzed by Spd/Spm acetyltransferase 1 or 2 (SAT1/2). [9][10][11] Levels of Spd and Spm are lower in 60-to 80-year-olds than in 31to 56-year-olds. 7 Spd and Spm have been shown to increase the lifespan of different species and improve neural functions via enhancement of autophagy in Caenorhabditis elegans, Drosophila, and mice.…”

mentioning

confidence: 89%

“…2,6 Human whole blood concentrations of Spd and Spm are kept strictly within the 4 to 40μM range. [9][10][11] Levels of Spd and Spm are lower in 60-to 80-year-olds than in 31to 56-year-olds. 12 In the rat cerebral cortex and human basal ganglia, the levels of Spd and Spm decrease with age.…”

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confidence: 89%

A metabolic profile of polyamines in parkinson disease: A promising biomarker

Saiki

Sasazawa

Fujimaki

et al. 2019

Annals of Neurology

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Objective Aging is the highest risk factor for Parkinson disease (PD). Under physiological conditions, spermidine and spermine experimentally enhance longevity via autophagy induction. Accordingly, we evaluated the ability of each polyamine metabolite to act as an age‐related, diagnostic, and severity‐associated PD biomarker. Methods Comprehensive metabolome analysis of plasma was performed in Cohort A (controls, n = 45; PD, n = 145), followed by analysis of 7 polyamine metabolites in Cohort B (controls, n = 49; PD, n = 186; progressive supranuclear palsy, n = 19; Alzheimer disease, n = 23). Furthermore, 20 patients with PD who were successively examined within Cohort B were studied using diffusion tensor imaging (DTI). Association of each polyamine metabolite with disease severity was assessed according to Hoehn and Yahr stage (H&Y) and Unified Parkinson's Disease Rating Scale motor section (UPDRS‐III). Additionally, the autophagy induction ability of each polyamine metabolite was examined in vitro in various cell lines. Results In Cohort A, N8‐acetylspermidine and N‐acetylputrescine levels were significantly and mildly elevated in PD, respectively. In Cohort B, spermine levels and spermine/spermidine ratio were significantly reduced in PD, concomitant with hyperacetylation. Furthermore, N1,N8‐diacetylspermidine levels had the highest diagnostic value, and correlated with H&Y, UPDRS‐III, and axonal degeneration quantified by DTI. The spermine/spermidine ratio in controls declined with age, but was consistently suppressed in PD. Among polyamine metabolites, spermine was the strongest autophagy inducer, especially in SH‐SY5Y cells. No significant genetic variations in 5 genes encoding enzymes associated with spermine/spermidine metabolism were detected compared with controls. Interpretation Spermine synthesis and N1,N8‐diacetylspermidine may respectively be useful diagnostic and severity‐associated biomarkers for PD. ANN NEUROL 2019;86:251–263

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“…In both cases, SARS-CoV-2 growth was reduced by 70%, suggesting that both compounds exhibit long-lasting antiviral effects, and supporting further investigation into prophylactic use of these compounds. For clinical use, half-maximal inhibitory concentration (IC50) of compounds should be in a non-toxic range and reach adequate plasma levels ( 35 ). The IC50 was 149 μM (R 2 = 0.71) for spermidine, 0.09 μM (R 2 = 0.95) for MK-2206, and 0.17 μM (R 2 = 0.63) for niclosamide, based on plaque-forming infectious units ( Figure 4c) .…”

Section: Fig1mentioning

confidence: 99%

Analysis of SARS-CoV-2-controlled autophagy reveals spermidine, MK-2206, and niclosamide as putative antiviral therapeutics

Gassen

Papies

Bajaj

et al. 2020

Preprint

117

147

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21Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses an acute threat to public health 22 and the world economy, especially because no approved specific drugs or vaccines are available. 23Pharmacological modulation of metabolism-dependent cellular pathways such as autophagy reduced 24 propagation of highly pathogenic Middle East respiratory syndrome (MERS)-CoV. 25Here we show that SARS-CoV-2 infection limits autophagy by interfering with multiple metabolic 26 pathways and that compound-driven interventions aimed at autophagy induction reduce SARS-CoV-2 27 propagation in vitro. In-depth analyses of autophagy signaling and metabolomics indicate that SARS-28 CoV-2 reduces glycolysis and protein translation by limiting activation of AMP-protein activated kinase 29 (AMPK) and mammalian target of rapamycin complex 1 (mTORC1). Infection also downregulates 30 autophagy-inducing spermidine, and facilitates AKT1/SKP2-dependent degradation of autophagy-31 initiating Beclin-1 (BECN1). Targeting of these pathways by exogenous administration of spermidine, 32AKT inhibitor MK-2206, and the Beclin-1 stabilizing, antihelminthic drug niclosamide inhibited SARS- 33CoV-2 propagation by 85, 88, and >99%, respectively. In sum, SARS-CoV-2 infection causally diminishes 34 autophagy. A clinically approved and well-tolerated autophagy-inducing compound shows potential 35 for evaluation as a treatment against SARS-CoV-2. 36 37 38 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint this version posted April 15, 2020. . https://doi.org/10.1101 3 The current pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses an 39 imminent threat to global health. As of 15 April 2020, 1,878,489 individuals were infected in >200 40 countries, with >119,000 fatalities (1). SARS-CoV-2 infections cause CoV-associated disease 19 (COVID-41 19), which can lead to severe atypical pneumonia in humans (2). Currently, there are no approved 42 therapeutics or vaccines available. The development and licensing of new FDA-approved drugs takes 43 years, which is problematic given the urgent need for effective therapies against novel, rapidly 44 emergent diseases like COVID-19. Antiviral drug screenings are commonly based on testing FDA-45 approved compound libraries against cellular and viral components (3). However, these undirected 46 approaches lack functional insights into how the drugs affect virus propagation. Risk evaluations for 47 drug repurposing and development of new therapeutics would benefit from rational drug design 48 founded on known SARS-CoV-2-host interactions. 49 Compound-based targeting of cellular proteins that are essential for the virus life cycle has led to the 50 discovery of broadly reactive drugs against a range of CoVs (3-6). As virus propagation strongly 51 depends on energy and catabolic substrates of host cells, drug target identification should consider 52 the metabolism of infected cells (3)....

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Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline

Cited by 114 publications

References 38 publications

Autophagy in T cells from aged donors is maintained by spermidine, and correlates with function and vaccine responses

Autophagy in T cells from aged donors is maintained by spermidine, and correlates with function and vaccine responses

A metabolic profile of polyamines in parkinson disease: A promising biomarker

Analysis of SARS-CoV-2-controlled autophagy reveals spermidine, MK-2206, and niclosamide as putative antiviral therapeutics

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